Heterogeneity of drug resistance in human breast and ovarian cancers.
OBJECTIVE
This study quantitates the extent of heterogeneity of drug resistance in breast and ovarian cancers. Identification of drug-specific resistance in tumors from multiple sites provides information necessary to understand the unique biology of a patient's disease.


METHODS
Drug resistance to cisplatin, paclitaxel, and doxorubicin was measured in multiple synchronous or metachronous tumors using the extreme drug resistance (EDR) assay. The degree of resistance for each tumor was classified into one of three categories: low drug resistance (LDR), EDR, or intermediate drug resistance (IDR).


RESULTS
When tested against cisplatin, 66% of primary ovarian cancers and their paired synchronous distant metastases (N = 88) shared the same resistance category, while 4% of the results were discordant (one site had EDR and the other site had LDR). Of the paired results for paclitaxel (N = 68), 54% were in the same resistance category, while 13% of the comparisons were discordant. Heterogeneity of drug response to cisplatin was also measured in primary ovarian cancers and paired recurrent tumors from 108 women. Median time to recurrence was 9.6 months. Only 55% of the paired results fell into the same resistance category, while 19% of the results were discordant. Drug resistance to doxorubicin was measured in primary breast cancers and paired synchronous metastases from 23 women: 74% of the paired results fell into the same resistance category, while 13% of the results were discordant. Metastatic sites had a slightly higher incidence of EDR than primary sites (26% and 17%, respectively). Heterogeneity of drug response to doxorubicin was then determined in primary breast cancers and paired recurrent tumors from 26 women with a median time to recurrence of 14.3 months. Only 52% of the paired results fell into the same resistance category, while 24% of the results were discordant.


CONCLUSIONS
Heterogeneity of drug resistance for ovarian and breast cancer is a serious clinical problem encountered in administering chemotherapy for overt metastatic or recurrent cancers. The first step in managing this problem is to recognize that heterogeneity of drug resistance exists. Drug resistance tests may then help the physician avoid administering certain chemotherapeutic agents when a patient's metastatic or recurrent tumor is found to be resistant to those agents.
Kern
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Oncotech, Inc., Irvine, CA 92714, USA.
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003520:Cyclophosphamide / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D009362:Neoplasm Metastasis; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000188:drug therapy* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology
D000970:Antineoplastic Agents; D004317:Doxorubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil